Analogs of cocaine

ABSTRACT

The invention provides a compound of formula (I):  
                 
 
     wherein R 1 , R 2 , R 3 , and Y have any of the meanings defined in the specification; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson&#39;s disease or depression comprising administering a compound of formula I, to a mammal in need of such treatment.

PRIORITY OF INVENTION

[0001] This application claims priority under 35 U.S.C. §119(e) fromU.S. Provisional Patent Application Number 60/042,775, filed Apr. 7,1997.

GOVERNMENT FUNDING

[0002] The invention described herein was made with U.S. Governmentsupport under grant DA11546 awarded by the National Institutes ofHealth, National Institute on Drug Abuse.

BACKGROUND OF THE INVENTION

[0003] Cocaine abuse is one of the greatest concerns of the Americanpublic today, and has therefore become a focus of medical, social andpolitical leaders. Cocaine is one of the most addictive substancesknown, and addicts may lose their ability to function at work or ininterpersonal situations. Drug dependence and the great profits that aremade throughout the distribution network of cocaine have fueled a risein drug-associated crime in the United States and in Colombia. Althoughthe incidence of casual cocaine use has decreased substantially in thelast few years, the number of weekly users is rising. The rise hasaccompanied a change in the chemical form often used to free base, or“crack,” and the route of administration used from nasal to inhalationby smoking or intravenous injection.

[0004] Psychological and behavioral approaches are important in atreatment program because peer pressure and environmental cues areclosely associated with a relapse to addiction. However, behavioralobservations have identified a window of about ten weeks after cessationof cocaine use where the susceptibility to relapse is greatest. Clearly,there is a need to increase the success rate of outpatientdetoxification programs through the development of pharmacologicalagents that will assist during this critical period.

[0005] Currently a number of treatment strategies are being looked atusing CNS agents developed for other indications. The agents being triedinclude, among others, the indirect dopamine agonist, amantadine, thedirect agonist bromocriptine, the partial mu opiate receptor agonist,buprenorphine, and the tricyclic antidepressant, desipramine. Whilethese agents appear to depress either self-administration or cocaine“craving” under certain circumstances, these studies are still in theirearly stages and the efficacy of such treatments has not beenestablished.

[0006] The behavioral properties of cocaine, including its abilities toact as a reinforcer, are thought to stem from its ability to inhibit thereuptake of dopamine (DA). While cocaine also has the ability to act asan inhibitor of serotonin and norepinephrine uptake as well as to bindto sigma opiate and muscarinic receptors, the potencies of cocaine andanalogs in self-administration studies correlate best with their DAtransporter inhibitor activities. Unfortunately, the precise mechanismby which cocaine inhibits dopamine uptake is still uncertain. Severallaboratories have shown that cocaine inhibition of dopamine uptake intostriatal synaptosomes is consistent with a classic, fully competitivemechanism. However these data are also consistent with more complexmodels, including allosteric or partially competitive, and severalothers involving steric hindrance, distinct but overlapping sites ormultiple binding sites in which at least one is required for bothcocaine and dopamine binding. In addition, a recent study using rotatingdisk electrode voltammetry, which is capable of monitoring uptake with a50 msec resolution, suggests that cocaine inhibits dopamine uptakeuncompetitively while competitively blocking Na⁺ and Cl⁻ binding to thecarrier. While these data have not been validated using otherexperimental approaches, they further support the idea that the cocaineand dopamine binding sites are unique.

[0007] N-Ethylmaleimide (NE) is capable of inhibiting about 95% of thespecific binding of [³H]mazindol, and the effect of 10 mMN-ethylmaleimide is completely prevented by 10 μM cocaine, while neither300 μM dopamine nor d-amphetamine afforded any significant protection.Furthermore, a recent study of the structure of the dopamine transporterrevealed that aspartate and serine residues lying within the first andseventh hydrophobic putative membrane spanning regions were critical fordopamine uptake, but less so for [³H]CFT (WIN-35428) binding. Forexample, replacement of the serine residues at positions 356 and 359 inthe seventh hydrophobic region by alanine or glycine reduced [³H]DAuptake, whereas [³ H]CFT (WIN-35428) binding was less affected. Morerecent experiments with DA and NE transporter chimeras show thattransmembrane domains 6-8 determine cocaine binding while domains 9-12plus the carboxy tail are responsible for DA binding affinity. Thus,these data support the hypothesis that a significant portion of thecocaine binding domain on the dopamine transporter is distinct from thatof either dopamine or amphetamine. This distinction may be sufficient toallow properly designed drugs to prevent cocaine binding withoutinhibiting dopamine uptake.

[0008] The most promising agents for treating cocaine abuse, may beagents which possess the ability to mimic partially the effects ofcocaine, thereby helping to maintain individuals in treatment programswhile they slowly withdraw from cocaine. Such an agent would functionlike methadone, a drug widely used in the treatment of opiate abuse. Acompound with methadone-type activity against cocaine abuse is likely tobe a partial agonist of cocaine; namely, a substance that elicits someof the same effects in the user as cocaine itself, but without causingthe same degree of euphoria. Ideally, the compound should have little orno abuse liability.

[0009] Thus there is currently a need for therapeutic agents that can beused to treat cocaine abuse.

SUMMARY OF THE INVENTION

[0010] The present invention provides a compound of formula (I):

[0011] wherein

[0012] Y is NR⁶, —C(R⁴)(R⁵)—, or —O—;

[0013] R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1,2,4-oxadiazol-5-yl optionallysubstituted at the 3-position by W, wherein any (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl may optionally besubstituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro,cyano, hydroxy, (C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b),C(═O)NR_(c)R_(d), NR_(e)R_(f), or S(═O)_(n)R_(g); and R³ is(C₆-C₁₀)aryl, 5-10 membered heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10membered heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10 memberedheteroarylcarbonyl, wherein any aryl or heteroaryl substituent mayoptionally be substituted on carbon by 1, 2 or 3 Z; or

[0014] R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to a carbon atthe ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10 memberedheteroaryl;

[0015] R² is hydrogen or (C₁-C₆)alkyl;

[0016] R⁴ and R⁵ are independently hydrogen or (C₁-C₆)alkyl;

[0017] R⁶ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or S(O)₂R_(h);

[0018] n is 0, 1 or 2;

[0019] W is (C₁-C₆)alkyl, or phenyl, optionally substituted by 1, 2, or3 Z;

[0020] R_(a) to R_(g) are independently hydrogen or (C₁-C₆)alkyl; and

[0021] R_(h) is H, (C₁-C₆)alkyl, or phenyl; or a pharmaceuticallyacceptable salt thereof.

[0022] Unexpectedly, it has been found that compounds of formula (I) canbind to the cocaine recognition site with an affinity comparable to thatof cocaine; additionally, the compounds also act as potent inhibitors ofdopamine uptake. It has been observed in drug discrimination studies inrats, that such compounds exhibit only weak cocaine- andamphetamine-like effects. The compounds of the invention thus appear topartially mimic cocaine's discriminative stimulus effects. Of furthernote are the results obtained from intravenous drug self-administrationstudies carried out using rats. In these studies, the animals trained toself-administer cocaine failed to self-administer the present compounds.In locomotor activity studies the compounds were found to have weakmotor stimulant effects. Compounds with these properties may be usefulfor treating drug abuse or for treating disorders wherein modulation ofdopamine or serotonin uptake is desired.

[0023] The invention also provides a pharmaceutical compositioncomprising a compound of formula I as described herein; or apharmaceutically acceptable salt thereof; in combination with apharmaceutically acceptable diluent or carrier.

[0024] The invention also provides a method comprising treating drug(e.g. cocaine) addiction in a human by administering a pharmaceuticallyeffective dose of a compound of formula I; or a pharmaceuticallyacceptable salt thereof.

[0025] The invention also provides a method for treating a disease orcondition in a mammal in which the activity of dopamine or serotonin isimplicated and modulation of dopamine or serotonin reuptake is desired(e.g. Parkinson's disease or depression), comprising administering acompound of formula I; or a pharmaceutically acceptable salt thereof.

[0026] The invention also provides a compound of formula I; or apharmaceutically acceptable salt thereof; for use in medical therapy ordiagnosis.

[0027] The invention also provides the use of a compound of formula I;or a pharmaceutically acceptable salt thereof; to prepare a medicamentuseful for treating drug (e.g. cocaine) addiction, Parkinson's disease,or depression.

[0028] The invention also provides a radiolabeled compound comprising aradionuclide and a compound of formula I; or a pharmaceuticallyacceptable salt thereof, as well as methods for using such aradiolabeled compound as an imaging agent (e.g. to identify, or evaluatethe function of, neurotransmitter binding sights in the brain of amammal, such as a human).

[0029] The invention also provides a method comprising binding acompound of formula I to mammalian tissue comprising dopamine receptors,in vivo or in vitro, by contacting said tissue with an amount of acompound of formula I effective to bind to said receptors. Tissuecomprising dopamine receptors with compounds of formula I bound theretocan be used as a pharmacologic tool to identify potential therapeuticagents for the treatment of diseases or conditions associated withdopamine function, by contacting the agents with the tissue, andmeasuring the extent of displacement of the compound of formula I and/orbinding of the agent. Tissue comprising dopamine receptors withcompounds of formula I bound thereto can also be used generally toelucidate the physiological function of neurotransmitters.

BRIEF DESCRIPTION OF THE FIGURES

[0030] FIGS. 1-10 Illustrate the synthesis of representative compoundsof the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl,etc. denote both straight and branched groups; but reference to anindividual radical such as “propyl” embraces only the straight chainradical, a branched chain isomer such as “isopropyl” being specificallyreferred to. Aryl denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic. Heteroaryl encompasses a radical attachedvia a ring carbon of a monocyclic aromatic ring containing five or sixring atoms consisting of carbon and one to four heteroatoms eachselected from the group consisting of non-peroxide oxygen, sulfur, andN(X) wherein X is absent or is H, O, (C₁-C₄)alkyl, phenyl or benzyl, aswell as a radical of an ortho-fused bicyclic heterocycle of about eightto ten ring atoms derived therefrom, particularly a benz-derivative orone derived by fusing a propylene, trimethylene, or tetraethylenediradical thereto.

[0032] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis, from optically active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine the relevant pharmacologicalproperties of the compound using the standard tests described herein, orusing other similar tests which are well known in the art.

[0033] Specific values listed below for radicals, substituents, andranges, are for illustration only and they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents

[0034] Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy,iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy; (C₂-C₆)alkenylcan be vinyl or allyl; (C₂-C₆)alkynyl can be ethynyl, 1-propynyl, or3-propynyl; (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;(C₂-C₆)acyloxy can be acetoxy, ethylcarbonyloxy or propylcarbonyloxy.Likewise, aryl can be phenyl, indenyl, or naphthyl. Heteroaryl can befuryl, imidazolyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl,pyrimidinyl (or its N-oxide), indolyl, or quinolyl (or its N-oxide).

[0035] A specific value for Y is NR⁶; wherein R⁶ is hydrogen,(C₁-C₆)alkyl or (C₁-C₆)alkanoyl.

[0036] A specific value for R¹ is (C₁-C₆)alkyl, which may optionally besubstituted by 1, 2 or 3 Z. Another specific value for R₁ is—C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the3-position by W. Another specific value for R¹ is cyano, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W. Anotherspecific value for R¹ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or(C₂-C₆)alkynyl. Another specific value for R¹ is —C(═O)OR_(a); whereinR_(a) is (C₁-C₄)alkyl.

[0037] A specific value for R² is hydrogen.

[0038] A specific value for R³ is benzyl, wherein the phenyl ring mayoptionally be substituted on carbon by 1, 2 or 3 Z. Another specificvalue for R³ is phenethyl, wherein the phenyl ring may optionally besubstituted on carbon by 1, 2 or 3 Z. Another specific value for R³ is5-10 membered heteroaryl, or 5-10 membered heteroaryl(C₁-C₆)alkyl,wherein any heteroaryl substituent may optionally be substituted oncarbon by 1, 2 or 3 Z. Another specific value for R³ is (C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, or (C₆-C₁₀)arylcarbonyl, wherein any arylsubstituent may optionally be substituted on carbon by 1, 2 or 3 Z.

[0039] Specifically R⁴ and R⁵ are each independently hydrogen.

[0040] A specific value for R⁶ is hydrogen, (C₁-C₆)alkyl or(C₁-C₆)alkanoyl. Another specific value for R⁶ is methyl or ethyl.Another specific value for R⁶ is hydrogen.

[0041] A specific value for R_(a) is methyl or ethyl.

[0042] A specific group of compounds are compounds of formula I wherenR¹ is 2,4-oxadiazol-5-yl, optionally substituted at the 3-position by W.

[0043] Another specific group of compounds are compounds of formula Iwheren R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionallysubstituted at the 3-position by W, wherein any (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl may optionally besubstituted by 1, 2 or 3 Z, wherein each Z is independently nitro,cyano, (C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; or a pharmaceutically acceptable salt thereof;provided that R³ is not phenyl, when R¹ is methoxycarbonyl oracetoxymethyl, R² is hydrogen, Y is NR⁶, and R⁶ is methyl.

[0044] Another specific group of compounds are compounds of formula Iwheren R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionallysubstituted at the 3-position by W, wherein any (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl may optionally be substituted by 1, 2or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy,(C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d),NR_(e)R_(f), or S(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 memberedheteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 memberedheteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10 memberedheteroarylcarbonyl, wherein any aryl or heteroaryl substituent mayoptionally be substituted on carbon by 1, 2 or 3 Z; or R¹ is —CH₂—, or—CH₂CH₂—, wherein R¹ is attached to a carbon at the ortho position ofR³; and R³ is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl; or apharmaceutically acceptable salt thereof; provided that R³ is notphenyl, when R¹ is methoxycarbonyl, R² is hydrogen, Y is NR⁶, and R⁶ ismethyl.

[0045] Another specific group of compounds are compounds of formula Iwheren Y is —C(R⁴)(R⁵)—, or —O—; or a pharmaceutically acceptable saltthereof.

[0046] Another specific group of compounds are compounds of formula Iwheren R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionallysubstituted at the 3-position by W; and R³ is (C₆-C₁₀)aryl, 5-10membered heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 memberedheteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10 memberedheteroarylcarbonyl, wherein any aryl or heteroaryl substituent mayoptionally be substituted on carbon by 1, 2 or 3 Z; or R¹ is —CH₂—, or—CH₂CH₂—, wherein R¹ is attached to a carbon at the ortho position ofR³; and R³ is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl; or apharmaceutically acceptable salt thereof; provided that R³ is notphenyl, when R¹ is methoxycarbonyl, R² is hydrogen, Y is NR⁶, and R⁶ ismethyl.

[0047] A specific group of compounds are compounds of formula I whereinR¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl, wherein any (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl may optionally be substituted by 1, 2or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy,(C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d),NR_(e)R_(f), or S(═O)_(n), R_(g); and R³ is phenyl which may optionallybe substituted on carbon by 1, 2 or 3 Z.

[0048] A preferred value for R³ is 4-chlorophenyl, 4-fluorophenyl,4-methylphenyl, or 4-isopropenylphenyl.

[0049] A preferred group of compounds are compounds of formula I whereinR¹ and R³ are in a trans configuration.

[0050] A preferred group of compounds are compounds of formula I whereinY is NR⁶; R¹ is methoxycarbonyl, (C₁-C₆)alkyl, or acetoxymethyl; R² ishydrogen; and R³ is 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or4-isopropenylphenyl; and R⁶ is methyl; or a pharmaceutically acceptablesalt thereof.

[0051] A preferred compound is (+)-methyl4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate; or apharmaceutically acceptable salt thereof.

[0052] Another preferred compound is (−)4β-(4-chlorophenyl)-1-methyl-3β-n-propylpiperidine; or (+)4β-(4-chlorophenyl)-1-methyl-3α-n-propylpiperidine; or apharmaceutically acceptable salt thereof.

[0053] Processes and intermediates useful for preparing compounds offormula I are provided as further embodiments of the invention and areillustrated by the following procedures.

[0054] As illustrated in FIG. 1, racemic piperidines 1 and 2 wereprepared starting from arecoline hydrobromide using chemistry similar tothat reported by Plati for the synthesis of the unsubstituted phenylbearing piperidine analogs (Plati, J. T.; Ingberman, A. K.; Wenner, W.Pyrilindene Derivatives. III. Synthesis from Arecoline. J. Org. Chem.1957, 22, 261-265).

[0055] Thus, the hydrobromide salt of arecoline was converted to itsfree base by sodium bicarbonate, and this intermediate subjected to aGrignard reaction using p-chlorophenylmagnesium bromide. A mixture ofthe cis- and trans-disubstituted piperidines 1 and 2 was produced in a75/25 ratio. The cis derivative was obtained by crystallization of thecrude material using EtOAc/hexane as solvent. The racemic transpiperidine was readily obtained by flash chromatography of the motherliquor.

[0056] The cis ester was resolved by use of (+)- and(−)-dibenzoyltartaric acid to provide the pure enantiomers (−)-3 and(+)-4 (Law, H.; Leclerc, G. A.; Neumeyer, J. L. An efficient andinexpensive resolution of the potent dopaminergic substance3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (±)-3-PPP. TetrahedronAsymm. 1991, 2, 989-992). An X-ray structure determination of the saltformed from (−)-dibenzoyltartaric acid and 1 was used to determine theabsolute stereochemistry of (−)-3 which is depicted in FIG. 1. As isapparent, the absolute stereochemistry of the (−)-isomer corresponds tothat found in the WIN series of structures.

[0057] The optically pure (+)- and (−)-cis esters were converted totheir respective alcohols (−)-5 and (+)-6 by lithium aluminum hydridereduction, and these alcohols were acylated with acetic anhydride in thepresence of pyridine to give acetate derivatives (−)-7 and (+)-8.Compound 9, wherein R¹ is propyl, was prepared from alcohol 5 byoxidation to the aldehyde followed by Wittig reaction and catalytichydrogenation. Compound 10 was prepared from the cis piperidine (−)-3 byhydrogenolysis over 10% palladium on charcoal in methanol at atmosphericpressure.

[0058] Because it was difficult to obtain satisfactory crystals from(±)-2 and dibenzoyltartaric acid, compounds (+)-11 and (−)-12 wereprepared by the base-catalyzed epimerization of compounds (−)-3 and(−)-4 as shown in FIG. 2. The more active isomer (+)-11 was converted tothe corresponding alcohol (+)-13 by reduction with lithium aluminumhydride in tetrahydrofuran. Acylation of alcohol (+)-13 with aceticanhydride and pyridine gave the acetate (+)-14. The n-propyl derivative(+)-15 was prepared by oxidation of alcohol (+)-13 followed by Grignardreaction using ethyltriphenyl-phosphonium bromide, and subsequenthydrogenation over 5% platinum on carbon.

[0059] As illustrated in FIG. 3, a compound of formula I wherein is R²(C₁-C₆)alkyl and R¹ is —C(═O)OR_(a) or cyano can be prepared from acorresponding compound of formula I wherein R² is hydrogen bydeprotonation followed by alkylation.

[0060] As illustrated in FIG. 4, compounds of formula I wherein R₃ issubstituted phenyl can be prepared using procedures similar to thosedescribed in: Carroll, F. I., Gao, Y., Rahman, M. A., Abraham, P.,Parham, K., Lewin, A. H., Boja, J. W., and Kuhar, M. J. (1991)Synthesis, ligand binding, QSAR and CoMFA study of 3b-(p-substitutedphenyl)tropane-2b-carboxylic acid methyl esters. J. Med. Chem., 34,2719-2725; or Blough, B. E., Abraham, P., Lewin, A. H., Kuhar, M. J.,Boja, J. W., and Carroll, F. I. (1996) Synthesis and transporter bindingproperties of 3b-(4′alkyl-, 4′-alkenyl-, and4′-alkynylphenyl)nortropane-2b-carboxylic acid methyl esters: serotonintransporter selective analogs. J. Med. Chem., 39, 4027-4035. Treatmentof arecoline with 4-trifluoromethylphenyl magnesium bromide in etherfollowed by chromatographic separation of the resulting isomers givescompound 18. Nitration of compound 19 with nitronium tetrafluoroborategives nitro compound 20, which can be reduced with Rany Ni to give amine21. Treatment of amine 21 with HONO followed by copper(I) bromide,potassium iodide or sodium azide gives compounds 22 a-c. Treatment ofamine 21 with acetyl chloride or ethyl chloroformate gives amide 23 a orcarbamate 23 b. Additionally, aryl iodide 22 b can be treated withisopropenyl zinc chloride in the presence of a palladium catalystbis(triphenylphosphine)palladium(II) chloride to yield isoprenylcompound 24.

[0061] As shown in FIG. 5, compounds of formula I wherein R¹ is —CH₂—,or —CH₂CH₂—, wherein R¹ is also attached to a carbon at the orthoposition of R³; and R³ is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl canbe prepared from a corresponding compound wherein R¹ is —C(═O)OR_(a).Treatment of methyl amine 25 with 1-chloroethyl chloroformate andmethanol, followed by p-toluenesulfonyl chloride in pyridine gives thetosyl amine 26. Reduction of the ester with lithium aluminum hydridefollowed by treatment with PBr₃ and cyclization with AlCl₃ givestricyclic compound 27 which can be deprotected by treatment withHBr/HOAc, and converted to the methyl amine 28 by reatment with withsodium hydroxide and formaldehyde, followed by reduction with sodiumcyanoborohydride.

[0062] As illustrated in FIG. 6, compounds of formula I wherein Y is—CH₂— or —O— may be prepared from the appropriatedihydropyran-3-carboxylate or cyclohexenecarboxylate using proceduressimilar to those described above for the preparation of thecorresponding compounds wherein Y is NR⁶.

[0063] As illustrated in FIG. 7, a compound of formula I wherein R⁶ is(C₁-C₆)alkyl or (C₁-C₆)alkanoyl (33) can be prepared from acorresponding compound of formula I wherein R⁶ is methyl by treatmentwith ACECl in refluxing methanol to give amine 32, followed byalkylation or acylation of the amine using standard conditions.

[0064] As shown in FIG. 8, a radiolabeled compound of formula I can beprepared by alkylation of an amine of formula 32 with a radiolabeledcompound (e.g. IC[³H]).

[0065] As shown in FIG. 9, compounds of formula I wherein R¹ is(C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl can be prepared usingprocedures similar to those described in Kozikowski, A. P., Saiah, M. K.E., Johnson, K. M., and Bergmann, J. S. (1995) Chemistry and biology ofthe 2b-alkyl-3b-phenyl analogues of cocaine: subnanomolar affinityligands that suggest a new pharmacophore model at the C-2 position. J.Med. Chem., 38, 3086-3093. Reduction of ester 11 with DIBAL followed byoxidation gives aldehyde 42. Treatment of compound 42 with a Grignardreagent gives an alkene of formula 43, which can be reduced withhydrogen over platinum on carbon to give an alkane of formula 44.

[0066] As illustrated in FIG. 10, a compound of formula I wherein R¹ isoxadiazolyl can be prepared by conversion of the ester group in acompound of formula I wherein R¹ is —C(═(O)OR_(a) to an acid, followedby acid chloride formation, and reaction with the appropriate amideoxime as described in: Kotian, P., Masearella, S. W., Abraham, P.,Lewin, A. H., Boja, J. W., Kuhar, M. J., and Carroll, F. I. (1996)Synthesis, ligand binding, and quantitative structure-activityrelationship study of 3b-(4′-substituted phenyl)-2b-heterocyclictropanes: evidence for an electrostatic interaction at the 2b-position.J. Med. Chem., 39, 2753-2763.

[0067] It is noted that many of the starting materials employed in thesynthetic methods described above are commercially available or arereported in the scientific literature, and that certain compounds offormula I are useful as intermediates to prepare other compounds offormula I.

[0068] In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable acid addition salts ofinorganic acids may also be formed, including hydrochloride, sulfate,nitrate, bicarbonate, and carbonate salts.

[0069] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

[0070] The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

[0071] Thus, the present compounds may be systemically administered,e.g., orally, in combination with a pharmaceutically acceptable vehiclesuch as an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0072] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0073] The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

[0074] The pharmaceutical dosage forms suitable for injection orinfusion can include sterile aqueous solutions or dispersions or sterilepowders comprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable copositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0075] Sterile injectable solutions are prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0076] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0077] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0078] Generally, the concentration of the compound(s) of formula I in aliquid composition, such as a lotion, will be from about 0.1-25 wt- %,preferably from about 0.5-10 wt- %. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt- %,preferably about 0.5-2.5 wt- %. Single dosages for injection, infuisionor ingestion will generally vary between 50-1500 mg, and may beadministered, i.e., 1-3 times daily, to yield levels of about 0.5-50mg/kg, for adults.

[0079] Compounds of the invention may also be used as imaging agentswhen labeled with a radionuclide. As illustrated in FIG. 9, theradionuclide (such as tritium, iodine-125, iodine-131, iodine-123,astatine-210, carbon-11, carbon-14, nitrogen-13, fluorine-18) may beincorporated into, or attached directly to the core structure, as byhalogenation; or the radionuclide (such as Tc-99m, Re-186) may beattached to a linking group or bound by a chelating group which is thenattached to the compound of formula I directly, or by means of a linker.Radiolabeling techniques such as these are routinely used inradiopharmaceutical chemistry.

[0080] Radiolabeled compounds of the invention are generally useful asimaging agents to diagnose neurological disease (e.g. aneurodegenerative disease) or a mental condition or to follow theprogression or treatment of such a disease or condition in a mammal(e.g. a human). The radiolabeled compounds of the invention and canconveniently be used in conjunction with imaging techniques suchpositron emission tomography (PET) or single photon emissioncomputerized tomography (SPECT).

[0081] The pharmacological activity of compounds of the invention can bedemonstrated using standard pharmacological models which are known inthe art, or can be demonstrated using the models that are described orcited hereinbelow.

[0082] Representative compounds of the invention 1-15 were tested fortheir ability to displace [³H]WIN-35428 binding from rat striatalmembranes and to inhibit the high-affinity uptake of [³H]dopamine intorat striatal nerve endings (synaptosomes) in accordance with protocolspreviously described by Boja et al. Mol Pharmacol. 1991, 39, 339. Theresults of these assays are provided in Table 1.

[0083] Table 1. IC₅₀ Values for Compounds of Formula I in [³H]WIN 35,428Binding and in the Inhibition of [³H]Dopamine Uptake

IC₅₀ (nM) [³H]WIN IC₅₀ (nM) Compound 35,428 [³H]dopamine number R Xbinding uptake cocaine — — 101.6 ± 9.4  239.1 ± 1.1  ±)-1 β-CO₂Me Cl53.7 ± 1.9  37.8 ± 7.9  (±)-2 α-CO₂Me Cl 196.8 ± 7.9  (−)-3 β-CO₂Me Cl24.8 ± 1.6  85.23 ± 2.6  (+)-4 β-CO₂Me Cl 1362 ± 125  5092 ± 172  (−)-5β-CH₂OH Cl 75.3 ± 6.2  49.0 ± 3.0  (+)-6 β-CH₂OH Cl 442 ± 32  — (−)-7β-CH₂OAc Cl 44.7 ± 10.5 62.9 ± 2.7  (+)-8 β-CH₂OAc Cl 928 ± 43  2027 ±82  (−)-9 β-nPr Cl 3.0 ± 0.5 8.3 ± 0.6 (−)-10 β-CO₂Me H 769 ± 19  —(+)-11 α-CO₂Me Cl 57.3 ± 8.1  34.6 ± 3.2  (−)-12 α-CO₂Me Cl 653 ± 38 195 ± 8  (+)-13 α-CH₂OH Cl 240 ± 18  683 ± 47  (+)-14 α-CH₂OAc Cl 461 ±11  — (+)-15 α-nPr Cl 17.2 ± 0.5  23.2 ± 2.2 

[0084] Analog Binding at Neurotransporters

[0085] Determination of inhibitory binding potencies of analogues atdopamine, serotonin, and norepinephrine transporters can be carried outusing standard receptor binding assays which are known in the art.

[0086] A. Dopamine Transporter Binding

[0087] Dopamine transporters can be assayed using the method describedby Boja, J. W., Rahman, M. A., Philip, A., Lewin, A. H., Carroll, F. I.and Kuhar, M. J. (1991) Isothiocyanate derivatives of cocaine:Irreversible of ligand binding at the dopamine transporter. MolPharmacol. 39, 339.

[0088] B. Serotonin Transporter Binding

[0089] Inhibition of [³H]binding to the serotonin transporter can beassayed according to previously published methods: Boja, J. W., Rahman,M. A., Philip, A., Lewin, A. H., Carroll, F. I. and Kuhar, M. J. (1991)Isothiocyanate derivatives of cocaine: Irreversible of ligand binding atthe dopamine transporter. Mol. Pharmacol., 39, 339.

[0090] C. Norepinephrine Transporter Binding

[0091] Binding to the norepinephrine transporter can be assayed using amethod described by Carroll, F. I., Grey, J., Abraham, P., Kuzemko, M.A., Lewin, A. H., Boja, J. W., and Kuhar, M. J. (1993)3-Aryl-2-(3′-substituted-1′,2′,4′-oxadiazole-5′-yl)tropane analogues ofcocaine: Affinities at the cocaine binding site at the dopamine,serotonin, and norepinephrine transporters. J. Med Chem., 36 2886-2890.

[0092] Uptake Studies

[0093] A. [³H]Dopamine Uptake Studies

[0094] Inhibition of [³H]dopamine uptake can be determined using themethod of Boja, J. W., McNeil, R. M., Lewin, A. H., Abraham, P.,Carroll, F. I., and Kuhar, M. J. (1992) Selective dopamine transporterinhibition by cocaine analogs. Neuroreport, 3, 984.

[0095] B. [³ H]Serotonin Uptake Studies

[0096] Inhibition of [³H]serotonin uptake can be determined in fresh rathind brain tissue. The assay can be conducted as described above, withsome modifications. The final tissue concentration will be approximately2 mg/mL, and the final [³H]serotonin concentration will be 5.0 nM.Non-specific uptake of [³H]serotonin can be defined using 1 μMcitalopram.

[0097] C. [³H]Norepinephrine Uptake Studies

[0098] Inhibition of [³H]norepinephrine uptake can be determined infresh rat cortex. The assay can be conducted in a manner similar to thatdescribed for [³H]dopamine uptake studies, with some modifications. Thefinal tissue concentration will be approximately 10 mg/mL, and the final[³H]norepinephrine concentration will be 5.0 nM. The non-specific uptakeof [³H]norepinephrine can be defined using 1 μM desipramine.

[0099] Intravenous Safety

[0100] Cocaine and a number of other tropane analogs are potentinhibitors of norepinephrine re-uptake and possess local anestheticactions. These properties may indicate significant potential forcardiovascular and central nervous system toxicity.

[0101] The test compounds with 10 μM or greater affinity for thedopamine transporter can be tested in rats for intravenous safetyaccording to the previously published procedure. Tella, S. R., Korupolu,G. R., Schindler, C. W., and Goldberg, S. R. (1992) Pathophysiologicaland pharmacological mechanisms of acute cocaine toxicity in consciousrats. J. Pharmacol. Exp. Ther., 262, 936-946.

[0102] Behavioral Testing

[0103] A. Locomotor Activity

[0104] The locomotor effects of compound 2 were evaluated using maleSwiss Webster mice according to previously published procedures:Izenwasser, S., Terry, P., Heller, B., Witkin, J. M., and Katz, J. L.(1994) Differential relationships among dopamine transporter affinitiesand stimulant potencies of various uptake inhibitors. Eur. J.Pharmacol., 263, 277-283.

[0105] Cocaine (10 mg/kg, i.p.) produced a significant (P<0.05) increasein the distance traveled and stereotypic behavior as compared to salinecontrol responses in Sprague-Dawley rats. In contrast to cocaine,piperidine analog 2 (3-20 mg/kg i.p.) did not alter the distancetraveled. However, piperidine 2 at 10 and 20 mg/kg doses produced asmall, statistically nonsignificant increase in stereotypic time. Thetime-course data indicate that this small increase in stereotypicbehavior is persistent at 90 minutes following the drug injection, whilethe stereotypic response to cocaine showed a clear tendency to declineat this time period. Thus the small behavioral responses to thepiperidine analog appear to last longer than that of cocaine. The motoreffects of higher doses of the piperidine analog were not tested asthese doses produce convulsions.

[0106] B. Drug-Discrimination

[0107] Compound 2 was evaluated in the drug discrimination proceduredescribed by: Callahan, P. M., Bryan, S. K., and Cunningham, K. A.(1995) Discriminative stimulus effects of cocaine: antagonism bydopamine D1 receptor blockade in the amygdala. Pharmacol. Biochem.Behav., 51, 759-766.

[0108] In Substitution tests, amphetamine administration engendered adose-dependent and complete substitution for the discriminative stimuluseffects of amphetamine, whereas administration of the piperidine analog2 resulted in a maximum of 53% amphetamine-lever responding. Responserates remained fairly stable across all test doses of amphetamine andpiperidine analog 2.

[0109] Cocaine (1.25-10 mg/kg) administration resulted in a dose-relatedincrease in cocaine-appropriate responding, whereas piperidine analog 2(5 and 20 mg/kg) engendered a maximum of 40% cocaine-lever responding.Response rates following piperidine analog 2 (5 and 10 mg/kg) weresubstantially lower than those observed following cocaine (10 mg/kg)administration. Co-administration of piperidine analog 2 (10 mg/kg) pluscocaine (1.25 and 5 mg/kg) did not significantly alter drug choice[F(1,7)=1.35, p=0.28] or response rate performance [F(1,7)=4.84, p=0.06]from that observed following administration of 1.25 and 5 mg/kg ofcocaine alone (data not shown). This result is in contrast to otherdopamine uptake inhibitors that are known to cause a leftward shift incocaine's dose-response function. These results suggest that thepiperidine analog differs from other uptake inhibitors in lacking thepotentiation of cocaine's discriminative stimulus effects.

[0110] C. Intravenous Drug Self-Administration

[0111] Compounds 2 and 3 were evaluated using the intravenous drugself-administration procedures described by: Tella, S. R., Ladenheim,B., Andrews, A. M., Goldberg, S. R., and Cadet, J. L. (1996)Differential reinforcing effects of cocaine and GBR-12909: Biochemicalevidence for divergent neuroadaptive changes in the mesolimbicdopaminergic system. J. Neurosci., 16, 7416-7427.

[0112] Rats were initially trained to lever press for food pellets instandard operant boxes. Following lever press training, rats wereimplanted with polyvinyl chloride catheters into femoral veins underhalothane anesthesia (2-3% in medical grade oxygen) and were allowed torecover for an additional 7 days before initiation of i.v. drugself-administration testing. During drug self-administration sessions,food pellets were no longer delivered, and instead intravenousinjections of drugs were delivered by way of the catheter. Eachcompletion of 10 lever press responses (FR10) resulted in an i.v.infusion of cocaine (1 mg/kg/infusion) delivered over a 1 second period.

[0113] Following approximately 3 weeks of cocaine self-administration,the extinction test was done by substituting saline (0.25 ml/kg) forcocaine for 5 days. Following extinction, re-acquisition of cocaine (1mg/kg/infusion) self-administration was tested for 5 days. Followingre-acquisition of cocaine self-administration, the saline extinctiontest was repeated. Following this second extinction test,self-administration of piperidine analog 2 was studied at doses of 1, 3,and 0.3 mg/kg/infusion in that order. Each dose was tested for fivedays. During all the re-acquisition test days, a priming infusion wasgiven at the start of the session on each day.

[0114] Cocaine maintained significantly (P<0.05) higher rates ofresponding as compared to the responding during the saline extinctiontest. The substitution of saline for cocaine led to a decline in theresponse rate. The substitution of piperidine analog 2 (0.3-3mg/kg/infusion) for saline failed to restore the self-administrationresponding. The number of infusions of the piperidine analog deliveredat all of the doses tested were not significantly different from that ofthe saline extinction test. These data suggest that the piperidineanalog, unlike cocaine, lacks positive reinforcing effects. In contrast,the piperidine analog 3 is cocaine-like in this test, as evidenced bythe fact that rats reliably self-administered this compound (0.125-0.5mg/kg infusion).

[0115] D. Effects of Test Compounds on Cocaine Self-Administration andFood Reinforcement

[0116] The effect of pretreatment with test compound on cocaineself-administration can be studied. Five minutes following intravenousinjection of test compounds, rats can be tested for cocaineself-administration. The doses that fall on both the ascending and thedescending portions of the cocaine dose-response function can be testedfollowing pretreatment with test compounds. This allows for adetermination of whether there is a left- or rightward shift or downwardshift in the cocaine dose-response function. Compounds showing overallreduction (downward shift) in cocaine self-administration can be furthertested for the specificity of this effect. This can be done by studyingthe effect of test compound on non-drug reinforcers such as food.

[0117] PET Evaluation

[0118] The cis and trans isomers of4-(4-chlorophenyl)-3-(carbomethoxy)piperidine were labeled viaN-methylation. ¹¹C-methyl iodide was bubbled into a solution of each ofthe piperidine isomers (1.5 mg free base in 0.3 cc DMSO) and themixtures were heated at 110° C. for 7 minutes. The products werepurified by HPLC on a C-18 cartridge eluted withMeOH:phosphate/triethylamine buffer, pH 7.2 (60:40). The ¹¹C-labeleddrugs were produced in good radiochemical yield [˜15% @EOS].Radiochemical purities of the final products were>98% and specificactivity were routinely >2,000 mCl/μmole [EOS].

[0119] After passage through a 0.22 μm filter, the sterile products wereadministered to three Rhesus monkeys and dynamic PET images wereacquired over 90 minutes. Both isomers accumulated rapidly in thestriatum with the cis isomer exhibiting greater nonspecific accumulationin the cortex. Studies with low specific activity tracer showed reducedstriatal-to-cerebellar ratios compared with high specific activitypreparations. When unlabeled CFT was administered 60 minutes afterinjection of the trans isomers, a selective decrease in the striatalactivity was observed; consistent with in vivo binding to the dopaminetransporter.

[0120] These results establish that both the cis- and trans isomers of4-(4-chlorophenyl)-3-carbomethoxy-N-methylpiperidine have high levels ofspecific binding to striatal dopamine transporter sites.

[0121] The 3-n-propyl derivative (−)-9 was found to have a bindingaffinity of 3 nM. Thus compound 9 is 33-fold more potent than cocaine inbinding affinity, and 29-fold more potent in its inhibition of dopamineuptake. The above results demonstrate that representative compounds offormula I possess significant binding activity at the dopamine receptor.Accordingly compounds of the invention may be useful as therapeuticagents for the treatment of drug abuse (e.g. cocain addiction).Additionally, compounds of formula I, and in particular, compoundswherein R⁶ is hydrogen, may also possess activity as serotonin reuptakeinhibitors. Accordingly, compounds of formula I may also be useful forinhibiting serotonin reuptake, and thus for treating Parkinson's diseaseor depression.

[0122] The invention will now be illustrated by the followingnon-limiting examples, wherein unless otherwise stated: startingmaterials were obtained from Aldrich Chemicals or from other commercialsuppliers; diethyl ether and cyclohexane were distilled from phosphoruspentoxide; tetrahydrofuran was freshly distilled under nitrogen fromsodium-benzophenone; infrared (“IR”) spectra were recorded on an ATIMattson Genesis spectrometer; proton ¹H and carbon ¹³C nuclear magneticresonance (“NMR”) spectra were obtained with a Varian Unity Inovainstrument at 300 and 75.46 MHz; ¹H chemical shifts (δ) are reported inppm downfield from internal TMS; ¹³C chemical shifts are referred toCDCl₃ (central peak, δ=77.0 ppm), benzene-d₆ (central peak, δ=128.0ppm), or DMSO-d₆ (central peak, δ=39.7 ppm); when appropriate NMRassignments were made with the help of COSY, DEPT, and HETCORexperiments; melting points were determined in Pyrex capillaries with aThomas Hoover Unimelt apparatus and are uncorrected; mass spectra weremeasured in the EI mode at an ionization potential of 70 eV; thin layerchromatography (“TLC”) was performed on Merck silica gel 60F₂₅₄ glassplates; column chromatography was performed using Merck silica gel(60-200 mesh); each of compounds 1-15 gave satisfactory combustionanalysis; and the following abbreviations are used: DMSO=dimethylsulfoxide; ether=diethyl ether; THF=tetrahydrofuran; andDCM=dichloromethane.

EXAMPLES Example 1 (±)-cis-Methyl4-(4-Chlorophenyl)-1-methylpiperidine-3 -carboxylate (1)

[0123] To a solution of 4-chlorophenylmagnesium bromide (166 mL, 1.0 Min ether) in ether (700 mL) was added dropwise at −10° C. a solution ofarecoline free base (12.9 g, 83 mmol, obtained from the hydrobromide bytreatment with sodium bicarbonate and extraction into methylenechloride) in ether (300 mL). The mixture was stirred at −10° C. for 30minutes, then poured onto crushed ice and treated slowly with 10% HCl(200 mL). The aqueous layer was separated, washed with ether (200 mL),and treated, while cooling in an ice bath, with a saturated solution ofsodium bicarbonate (100 mL). The mixture was extracted with ether (2×200mL), and the combined organic phases were washed with brine (200 mL),dried, and concentrated under reduced pressure. The crude mixture wascrystallized from EtOAc/hexane to afford the the title compound 1 (5.0g, 22%) as a white solid. Concentration of the mother liquor gave amixture of compounds 1 and 2 that was separated by flash chromatographyon silica gel using ether/Et₃N 9/1 as eluent to give additional titlecompound (total 12.4 g, 56%): mp 98-99° C.; ¹H NMR (CDCl₃) δ1.74-1.86(m, H_(5eq)), 2.07 (dt, H_(6ax), J=3.0 and 11.4 Hz), 2.28 (s, 3H), 2.35(dd, H_(2′), J=3.6 and 11.7 Hz), 2.66 (dq, H_(5ax), J=3.9 and 12.0 Hz),2.78 (dt, H₄, J=3.6 and 12.0 Hz), 2.9-3.06 (m, H₃ and H6eq), 3.18 (bd,H_(2″), J=12.0 Hz), 3.52 (s, 3H), 6.2-6.35 (m, 4H); ¹³C NMR (CDCl₃)δ26.42 (C₅), 41.27 (C₄), 46.06 (C₃), 46.53 (C₇), 51.25 (C₉), 55.88 (C₆),58.36 (C₂), 128.08 (C₁₁, C₁₅), 128.95 (C₁₂, C₁₄), 131.79 (C₁₃), 141.54(C₁₀), 172.47 (C₈); MS m/z (%) 267 (M⁺, 7), 208 (14), 128 (6), 70 (29),44 (100).

[0124] Compound 1 was dissolved in a methanolic solution of hydrochloricacid gas and the resulting solid was triturated with ether to givecompound 1·HCl: ¹H NMR (methanol-d₄) δ_(—)2.05 (bd, 1H, J=4.0 Hz), 2.53(bq, 1H, J=10.8 Hz), 2.94 (s, 3H), 3.14-3.5 (m, 4H), 3.45 (s, 3H),3.6-3.7 (m, 1H), 3.78 (d, 1H, J=12.9 Hz),_(—)7.22 (d, 2H, J=8.4 Hz),7.35 (d, 2H, J=8.4 Hz).

Example 2 (±)-cis-Methyl4-(4-Chlorophenyl)-1-methylpiperidine-3-carboxylate (2)

[0125] Concentration of the mother liquor from Example 1 gave a mixtureof compounds 1 and 2. Flash chromatography on silica gel usingether/Et₃N 9/1 as eluent gave compound 2 (2.0 g, 18%): ¹H NMR(bcnzene-d₆) δ_(—)1.4-1.5 (m, 1H),_(—)1.62 (dq, 1H, J=3.9 and 12.6 Hz),1.75 (dt, 1H, J=2.7 and 12.0 Hz), 2.06 (s, 3H), 2.0-2.15 (m, 1H),2.54-2.63 (m, 1H), 2.68 (dt, 1H, J=4.2 and 11.7 Hz), 2.86-3.0 (m, 2H),3.08 (s, 3H), 6.87 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.7 Hz); ¹³C NMR(CDCl₃) δ33.1, 44.0, 46.1, 49.1, 51.5, 55.7, 58.1, 128.6, 128.7, 132.3,141.9, 173.4; MS m/z (%) 267 (M⁺, 17), 208 (30), 128 (16), 114 (16), 43(100).

[0126] Using a procedure similar to that described in Example 1, thehydrochloride salt of compound 2 was prepared: compound 2·HCl: ¹H NMR(methanol-d₄) δ2.04-2.16 (m, 2H), 2.97 (s, 3H), 3.0-3.3 (m, 4H), 3.47(s, 3H), 3.56-3.66 (m, 1H), 3.7-3.8 (m, 1H), 7.25 (d, 2H, J=8.4 Hz),7.34 (d, 2H, J=

Example 3 (−)-Methyl4β-(4-chlorophenyl)-1-methylpiperidine-3β-carboxylate (3)

[0127] To a solution of compound 1 (6.4 g, 24 mmol) in MeOH (200 mL) wasadded a solution of dibenzoyl-L-tartaric acid (8.9 g, 24 mmol) in MeOH(100 mL). The resulting mixture was stirred at room temperature for 5hours, filtered, and the white precipitate washed with MeOH (20 mL).This tartrate salt was treated with a saturated solution of NaHCO₃ (150mL) and the mixture extracted with CHCl₃ (3×100 mL). The combinedorganic phases were washed with brine (150 mL), dried, and concentratedunder reduced pressure to afford the title compound (2.0 g) as a whitesolid: mp 98-99° C.; [α]²⁵ _(D) −56° (c 1.0, EtOH).

[0128] Using a procedure similar to that described in Example 1, thehydrochloride salt of compound 3 was prepared: compound 3·HCl; [α]²⁵_(D) −130° (c 1.0, EtOH).

[0129] Single Crystal X-Ray Analysis was preformed on the(−)-Dibenzoyltartrate of (3) as described below. A clear rectangular0.06×0.08×0.52 mm crystal, C₁₄H₁₉O₂ClN⁺ C₁₈H₁₃O₈ ⁻, FW=626.04, wasselected for data collection. Data were collected on a computercontrolled Siemens CCD 1K area detector system with a Siemens PLATFORMgoniometer using a Rigaku rotating anode source and Gobel mirrors (CuKα_radiation, λ=1.54178 Å, T=295 K). Data collection nominally covered ahemisphere in reciprocal space by combining six sets of exposures withdifferent 2θ and φ angles: each exposure covered a range of 0.75° in ω.The crystal to detector distance was 5.09 cm, and coverage of a uniqueset was 98% complete to 1.0 Å resolution. The crystal decay wasmonitored by repeating 50 of the initial frames at the end of datacollection and was found to be 2.7%. A least-squares refinement using176 centered reflections within 16.2<2θ<34.4° gave the orthorhombicP2₁2₁2₁ cell, a=7.752(3), b=14.691(5) c=27.502(8) Å, with V=3132.2 (17)Å³, Z=4, and d_(calc)=1.328 gm/cm³. A total of 8342 reflections were to2θ_(−max)=100°, of which there were 2923 independent reflections.Corrections were applied for Lorentz and polarization effects. Anempirical absorption correction was applied using equivalent reflections(SADABS), μ=1.577 mm⁻¹. Max. and min. transmission were 0.44 and 0.88,respectively. The structure was solved by direct methods with the aid ofthe program SHELXT1 and refined on F² with full matrix least-squares.The 398 parameters refined include the coordinates and anisotropicthermal parameters for all non-hydrogen atoms. Hydrogens were includedusing a riding model. The final R values for the 2244 observedreflections with F_(o)>4σ(|F_(o)|) were R=0.086 and wR(F²)=0.208. Thegoodness of fit parameter was 1.07, and final difference Fourierexcursions were 0.41 and −0.27 eÅ⁻³. The absolute configurationdetermination was based on a method suggested by D. Rogers. The absolutestructure parameter which should be near 0.0 for the correct choice ofchirality and 1.0 for an incorrect choice was 0.04(6). The compound alsocontained a chiral anion, (−)-dibenzoyltartaric acid.

Example 4 (+)-Methyl4β-(4-Chlorophenyl)-1-methylpiperidine-3β-carboxylate (4)

[0130] To the mixture of enantiomers derived from the mother liquor ofExample 3 (4.2 g, 15.7 mmol) in MeOH (150 mL) was added a solution ofdibenzoyl-D-tartaric acid (5.8 g, 15.7 mmol) in MeOH (50 mL). Theresulting mixture was stirred at oom temperature 5 hours, filtered, andthe white precipitate was washed with MeOH (10 mL). This tartrate saltwas treated with a saturated solution of NaHCO₃ (100 mL) and the mixtureextracted with CHCl₃ (3×70 mL). The combined organic phases were washedwith brine (150 mL), dried, and concentrated under reduced pressure toafford the title compound (2.2 g) as a white solid: mp 98-99° C.; [α]²⁵_(D) +56° (c 1.0, EtOH).

[0131] The hydrochloride salt was prepared by dissolution of the freebase of compound 4 in a methanolic solution of HCl(g), concentration,and final trituration of the crude salt with ether: [α]²⁵ _(D) +126° (c1.0, EtOH).

Example 5 (−)-4β-(4-Chlorophenyl)-3β-(hydroxymethyl)-1-methylpiperidine(5)

[0132] To a solution of 3 (1.0 g, 3.7 mmol) in THF (30 mL) was addedportionwise LiAlH₄ (0.3 g, 7.5 mmol). The resulting mixture was stirredat room temperature for 2 hours. A saturated solution of Rochelle salt(30 mL) was added followed by extraction with EtOAc (100 mL). Theorganic phase was washed with brine (100 mL), dried, and concentratedunder reduced pressure to afford the title compound (0.9 g, 98%) as acolorless oil: [α]²⁵ _(D) −70° (c 1.0, EtOH); ¹H NMR (CDCl₃) δ1.64-1.84(m, H₃ and H_(5eq)), 2.11 (dt, H_(6ax), J=3.3 and 11.7 Hz), 2.29 (s,3H), 2.45 (dt, H_(1′), J=2.7 and 11.4 Hz), 2.55 (dq, H_(5ax), J=4.2 and12.6 Hz), 2.84 (dt, H₄, J=4.5 and 13.5 Hz), 3.0-3.1 (m, H_(6eq)), 3.14(br d, H_(2″), J=11.4 Hz), 3.54 (dt, H₈, J=2.4 and 10.8 Hz), 3.70 (dd,H₈, J=3.3 and 11.1 Hz), 7.24 (d, 2H, J=8.7 Hz), 7.29 (d, 2H, J=8.7 Hz);¹³C NMR (CDCl₃) δ27.9 (C₄), 40.2 (C₂), 43.5 (C₃), 46.3 (C₆), 56.2 (C₁),61.4 (C₅), 64.5 (C₈), 128.4 (C₁₁, C₁₅), 129.2 (C₁₂, C₁₄), 131.9 (C₁₃),142.1 (C₁₀); MS m/z (%) 239 (M⁺, 6), 208 (6), 100 (16), 44 (100).

Example 6 (+)-4β-(4-Chlorophenyl)-3β-(hydroxymethyl)-1-methylpiperidine(6)

[0133] Using a procedure similar to that described in Example 5, exceptreplacing the compound 3 used therein with compound 4, the titlecompound 6 was prepared (82%) as a colorless oil; [α]²⁵ _(D) +67° (c 1;EtOH).

Example 7 (−)-3β-(Acetoxymnethyl)-4β-(4-chlorophenyl)-1-methylpiperidine(7)

[0134] To a solution of compound 5 (90 mg, 0.38 mmol) in pyridine (2 mL)was added acetic anhydride (0.5 mL). The resulting solution was stirredat room temperature for 15 hours, concentrated under reduced pressure,diluted with EtOAc (30 mL), and washed with a saturated solution ofNH₄Cl (2×20 mL). The organic solution was dried and concentrated underreduced pressure to afford the title compound (0.10 g, 95%) as a whitesolid: mp 76° C.; [α]²⁵ _(D) −109° (c 0.75; EtOH); R_(f) 0.6 (ether/Et₃N9.5/0.5); ¹H NMR (benzene-d₆) δ1.21 (br d, 1H, J=11.4 Hz), 1.52 (s, 3H),1.72 (dq, 1H, J=3.0 and 12.3 Hz), 1.6-1.7 (m, 1H), 1.86 (dd, 1H, J=2.7and 11.4 Hz), 2.0-2.1 (m, 1H), 2.09 (s, 3H), 2.40 (dt, 1H, J=3.9 and11.4 Hz), 2.67 (br d, 1H, J=8.1 Hz), 2.91 (d, 1H, J=11.4 Hz), 3.90 (dd,1H, J=4.5 and 10.8 Hz), 4.47 (dd, 1H, J=9.6 and 10.5 Hz), 6.68 (d, 2H,J=8.4 Hz), 7.09 (d, 2H, J=8.4 Hz); ¹³C NMR (CDCl₃) β20.8, 25.6, 39.6,41.9, 46.5, 56.2, 57.8, 62.5, 128.4, 128.5, 132.0, 141.5, 170.9; MS m/z(%) 281 (M⁺, 6), 238 (6), 208 (15), 142 (7), 44 (100).

Example 8 (+)-3β-(Acetoxymethyl)-4β-(4-chlorophenyl)-1-methylpiperidine(8)

[0135] Using a procedure similar to that described in Example 7, exceptreplacing compound 5 used therein with compound 6, the title compound 8was prepared (93%) as a white solid: [α]²⁵ _(D) +107° (c 0.35; EtOH); MSmrz (%) 281 (M⁺, 6).

Example 9 (−) 4β-(4-chlorophenyl)-1-methyl-3β-n-propylpiperidine (9)

[0136] Oxalyl chloride (0.19 mL) was dissolved in anhydrous CH₂Cl₂ (15mL), and the solution was cooled to −78° C. Dimethyl sulfoxide (0.32 mL)was added, after 5 minutes, alcohol 5 (0.5 g, 2.08 mmol) was added inCH₂Cl₂ (5 mL), and stirring was continued for 30 minutes. The reactionmixture was quenched by adding Et₃N (2.84 mL), and the resultingsolution was warmed to room temperature, diluted with CH₂Cl₂ (30 mL),washed with NH₄Cl (2×30 mL), dried, and concentrated under reducedpressure to provide the intermediate aldehyde (0.45 g, 91%) as acolorless oil used in the next step without further purification: ¹H NMR(CDCl₃) β1.9-2.0 (m, 1H), 2.10 (dt, 2H, J=2.4 and 11.4 Hz), 2.29 (s,3H), 2.2-2.4 (m, 2H), 2.64-2.74 (m, 1H), 2.92 (dt, 1H, J=3.9 and 12.9Hz), 3.0-3.1 (m, 1H), 3.28 (br d, 1H, J=11.4 Hz), 7.2 (d, 2H, J=8.4 Hz),7.29 (d, 2H, J=8.4 Hz), 8.7 (s, 1H), ¹³C NMR (CDCl₃) δ27.2, 40.9, 46.5,51.9, 55.9, 57.0, 128.6, 128.7, 132.3, 140.6, 203.9.

[0137] A solution of n-BuLi (2.28 mL, 1 M in hexane, 5.7 mmol) wasdissolved in THF (10 mL) and cooled to 0° C. Ethyltriphenylphosphoniumbromide (2.1 g, 5.7 mmol) was added slowly under nitrogen. The resultingyellow-orange solution was stirred at 0° C. for 30 minutes, and thecooling bath was removed. The crude aldehyde (0.45 g, 1.9 mmol) wasadded in THF (2 mL), and the reaction mixture was stirred for 15 hoursat room temperature, diluted with EtOAc (20 mL), and washed with asaturated solution of NH₄Cl (2×30 mL). The organic phase was extractedwith 10% HCl (3×10 mL). The combined aqueous phases were washed withEtOAc (30 mL), neutralized with a saturated solution of NaHCO₃, andextracted with CH₂Cl₂ (2×30 mL). The combined organic phases were driedand concentrated under reduced pressure, and the residue was purified byflash chromatography on silica gel using ether/Et₃N 9.5/0.5 as eluent toafford an olefin intermediate as a mixture of cis and trans isomers (0.3g, 63%): MS m/z (%) 248 (M⁺, 6), 57 (100).

[0138] To a solution of the olefins (0.2 g, 0.80 mmol) in cyclohexane(20 mL) was added 5% Pt/C (0.2 g). The mixture was stirred at roomtemperature for 30 minutes under H₂ (40 psi). The solution was filteredover celite and evaporated to dryness. The resulting colorless oil waspurified by flash chromatography on silica gel using ether/Et₃N 9.5/0.5as eluent to afford the title compound 9 (0.19 g, 94%) as a colorlessoil: [α]²⁵ _(D) −84° (c 0.5, EtOH); ¹H NMR (benzene-d₆) δ0.71 (t, 3H,J=6.9 Hz), 0.75-1.0 (m, 2H), 1.2-1.4 (m, 2H), 1.52-1.65 (m, 1H),1.65-1.84 (m, 2H), 1.84-2.0 (m, 2H), 2.14 (s, 3H), 2.47 (dt, 1H, J=3.6and 12.3 Hz), 2.7-2.84 (m, 1H), 6.77 (d, 2H, J=8.4 Hz), 7.15 (d, 2H,J=8.4 Hz); ¹³C NMR (CDCl₃) δ14.0, 21.1, 25.4, 27.6, 40.2, 43.9, 46.8,56.5, 59.4, 128.1, 128.8, 131.4, 142.9; MS m/z (%) 251 (M⁺, 8), 208 (8),112 (24), 44 (100).

[0139] The hydrochloride salt was prepared by dissolution of the freebase in a methanolic solution of HCl(g), concentration, and finaltrituration of the crude salt with ether: mp>230° C.; [α]²⁵ _(D) −73° (c0.25, EtOH); ¹H NMR (methanol-d₄) δ0.78 (t, 3H, J=6.6 Hz), 0.9-1.1 (m,2H), 1.28-1.5 (m, 2H), 1.94-2.06 (m, 1H), 2.14-2.38 (m, 2H), 2.92 (s,3H), 3.04-3.4 (m, 3H), 3.54-3.7 (m, 2H), 7.24 (d, 2H, J=7.8 Hz), 7.35(d, 2H, J=7.8 Hz).

Example 10 (−)-Methyl 1-Methyl-4β-phenylpiperidine-3β-carboxylate (10)

[0140] A mixture of compound 3 (0.7 g, 2.61 mmol) and 10% Pd/C (0.28 g)in MeOH (20 mL) was hydrogenated under 1 atm of H₂ for 3 hours. Theresulting mixture was filtered over celite and evaporated to dryness.The resulting pale yellow oil was purified by flash chromatography onsilica gel using ether/Et₃N 9.5/0.5 as eluent to afford the titlecompound (0.6 g, 98%) as a colorless oil: [α]²⁵ _(D) −54° (c 1; EtOH);¹H NMR (CDCl₃) δ1.76-1.9 (m, H_(5eq)) 2.09 (dt, H_(6ax), J=2.7 and 11.1Hz), 2.29 (s, 3H), 2.37 (dd, H_(2′), J=3.6 and 11.7 Hz), 2.70 (dq,H_(5ax), J=3.9 and 12.3 Hz), 2.85 (dt, H₄, J=3.9 and 11.7 Hz), 2.92-3.06(m, H₃ and H_(6eq)), 3.18 (br d, H_(2″), J=12.0 Hz), 3.50 (s, 3H),7.1-7.4 (m, 5H); ¹³C NMR (CDCl₃) δ26.6, 41.8, 46.2, 46.6, 51.2, 55.9,58.3, 126.1, 127.6, 128.0, 143.0, 172.7; MS m/z (%) 233 (M⁺, 13), 232(6), 174 (17), 70 (26), 44 (100).

[0141] The hydrochloride salt was prepared by dissolution of the freebase in a methanolic solution of HCl(g), concentration, and finaltrituration of the crude salt with ether:[α]²⁵ _(D) −130° (c 1.0, EtOH);mp 168-169° C.; ¹H NMR (methanol-d₄) δ2.0-2.1 (m, 1H), 2.5-2.7 (m, 1H),2.95 (s, 3H), 3.1-3.5 (m, 4H), 3.42 (s, 3H), 3.6-3.7 (m, 2H), 3.7-3.85(m, 1H), 7.2-7.4 (m, 5H).

Example 11 (+)-Methyl4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (11)

[0142] To a solution of compound 3 (0.5 g, 1.87 mmol) in MeOH (6 mL) wasadded a 30% methanolic solution of sodium methoxide (0.04 mL). Theresulting solution was stirred at reflux for 24 hours and concentratedunder reduced pressure. CH₂Cl₂ and brine were added, and the organiclayer was washed with brine. Concentration of the combined organic phaseafforded compound 3 and compound 11 in a 1:32 ratio (determined by GC-MSanalysis). Purification of the crude product by silica gel flashchromatography using ether/Et₃N 9.8/0.2 as eluent afforded the titlecompound (0.43 g, 86%) as a colorless oil: [α]²⁵ _(D) +46° (c 1.0,EtOH).

[0143] The hydrochloride salt was prepared by dissolution of the freebase in a methanolic solution of HCl(g), resulting in a directcrystallization of the desired salt: [α]²⁵ _(D) +55° (c 0.5, EtOH);mp >230 ° C.

Example 12 (−)-Methyl4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylate (12)

[0144] To a solution of compound 4 (0.4 g, 1.49 mmol) in MeOH (3 mL) wasadded a 30% methanolic solution of sodium methoxide (0.01 mL). Theresulting solution was stirred at reflux for 11 hours and concentratedunder reduced pressure. CH₂Cl₂ and a saturated solution of NH₄Cl wereadded. The organic layer was washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure to afford compounds 4and 12 in a 1:5.6 ratio (determined by GC-MS analysis). Purification ofthe crude product by silica gel flash chromatography using ether/Et₃N9.8/0.2 as eluent afforded the title compound (0.35 g, 85%) as acolorless oil: [α]²⁵ _(D) −50° (c 1.0, EtOH).

Example 13 (+)-4β-(4Cchlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine(13)

[0145] Using a procedure similar to that described in Example 5, exceptreplacing the compound 3 used therein with compound 11, the titlecompound was obtained (84%) as a colorless oil: [α]²⁵ _(D) +38° (c 0.5;EtOH); mp 148-150° C.; ¹H NMR (CDCl₃) δ1.4 (br s, OH), 1.7-2.1 (m, 5 H),2.29 (dd, 1 H, J=5.4 and 10.5 Hz), 2.36 (s, 3 H), 2.95 (d, 1 H, J=10.8Hz), 3.15 (d, 1 H, J=10.8 Hz), 3.24 (dd, 1 H, J=6.6 and 10.8 Hz), 3.41(dd, 1 H, J=3.0 and 10.8 Hz), 7.14 (d, 2 H, J=8.4 Hz), 7.27 (d, 2 H,J=8.4 Hz).

Example 14 (+)-3β-(Acetoxymethyl)-4β-(4-chlorophenyl)-1-methylpiperidine(14)

[0146] Using a procedure similar to that described in Example 7, exceptreplacing compound 5 used therein with compound 13, the title compoundwas obtained (80%) as a white solid: ¹H NMR (CDCl₃) δ1.7-1.9 (m, 3 H),1.97 (s, 3 H), 1.95-2.1 (m, 1 H), 2.1-2.3 (m, 2 H), 2.35 (s, 3 H), 2.95(d, 1 H, J=11.4 Hz), 3.07 (d, 1 H, J=9.6 Hz), 3.63 (dd, 1 H, J=7.5 and11.4 Hz), 3.82 (dd, 1 H, J=3.0 and 11.1 Hz), 7.12 (d, 2 H, J=8.4 Hz),7.27 (d, 2 H, J=8.4 Hz); ¹³C NMR (CDCl₃) δ20.7, 34.4, 41.0, 44.2, 46.4,56.0, 59.3, 65.2, 128.7, 128.8, 132.2, 142.1, 170.9.

Example 15 (+) 4β-(4-chlorophenyl)-1-methyl-3α-n-propylpiperidine (15)

[0147] Using a procedure similar to that described in Example 9, exceptreplacing compound 5 used therein with compound 13, the title compoundwas obtained (70%) as a colorless oil: [α]²⁵ _(D) +418 (c 1.0, EtOH); ¹HNMR (CDCl₃) δ0.73 (t, 3 H, J=7.2 Hz), 0.8-1.0 (m, 1 H), 1.0-1.2 (m, 2H), 1.2-1.4 (m, 1 H), 1.65 (t, 1 H, J=10.8 Hz), 1.7-1.9 (m, 3 H),1.9-2.15 (m, 2 H), 2.32 (s, 3 H), 2.93 (d, 1 H, J=11.1 Hz), 3.05 (d, 1H, J=10.8 Hz), 7.10 (d, 2 H, J=8.4 Hz), 7.25 (d, J=8.1 Hz); ¹³C NMR(CDCl₃) d 14.1, 19.7, 33.9, 35.0, 40.8, 46.5, 48.2, 56.3, 61.6, 128.5,129.0, 131.6, 143.8.

[0148] The hydrochloride salt was prepared by dissolution of the freebase in a methanolic solution of HCl(g), concentration, and finaltrituration of the crude salts with ether: [α²⁵ _(D) +348 (c 0.25,EtOH); mp 216° C. (EtOAc); ¹H NMR (methanol-d₄) δ0.77 (t, 3 H, J=6.9Hz), 1.0-1.4 (m, 4 H), 1.9-2.2 (m, 3 H), 2.56 (q, 1 H, J=10.8 Hz), 2.86(t, 1 H, J=12.6 Hz), 2.93 (s, 3 H), 3.0-3.2 (m, 1 H), 3.5-3.7 (m, 2 H),7.23 (d, 2 H, J=8.4 Hz), 7.35 (d, 2 H, J=8.4 Hz).

Example 16 The following Illustrate Representative Pharmaceutical DosageForms, Containing a Compound of Formula I (‘Compound X’), forTherapeutic or Prophylactic use in Humans

[0149] (i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg/tablet ‘Compound X’ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodiumhydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injectionq.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml ‘Compound X’ (free acidform) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1Polyethylene glycol 400 200.0 01 N Sodium hydroxide solution q.s. (pHadjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosolmg/can ‘Compound X’ 20.0 Oleic acid 10.0 Trichloromonofluoromethane5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane5,000.0

[0150] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art.

[0151] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein Y is NR⁶, —C(⁴)(R⁵)—, or —O—; R¹ is —C(═O)OF_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently nitro, cyano, (C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b),C(═O)NR_(c)R_(d), or S(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10membered heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 memberedheteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10 memberedheteroarylcarbonyl, wherein any aryl or heteroaryl substituent mayoptionally be substituted on carbon by 1, 2 or 3 Z; or R¹ is —CH₂—, or—CH₂CH₂—, wherein R¹ is attached to a carbon at the ortho position ofR³; and R³is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl; R² is hydrogenor (C₁-C₆)alkyl; R⁴ and R⁵ are independently hydrogen or (C₁-C₆)alkyl;R⁶ is hydrogen, (C₁-C₆)alkyl (C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1or 2; W is (C₁-C₆)alkyl, or phenyl, optionally substituted by 1, 2, or 3Z; R_(a) to R_(g) are independently hydrogen or (C₁-C₄)alkyl; and R_(h)is H, (C₁-C₄)alkyl, or phenyl; or a pharmaceutically acceptable saltthereof; provided that R³ is not phenyl, when R¹ is methoxycarbonyl oracetoxymethyl, R² is hydrogen, Y is NR⁶, and R⁶ is methyl.
 2. A compoundof formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl may optionally besubstituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro,cyano, hydroxy, (C₁-C₆)alkoxy, (C₂-C₆)acyloxy, C(═O)OR_(b),C(═O)NR_(c)R_(d), NR_(e)R_(f), or S(═O)_(n)R_(g); and R³ is(C₆-C₁₀)aryl, 5-10 membered heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10membered heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10 memberedheteroarylcarbonyl, wherein any aryl or heteroaryl substituent mayoptionally be substituted on carbon by 1, 2 or 3 Z; or R¹ is —CH₂—, or—CH₂CH₂—, wherein R¹ is attached to a carbon at the ortho position ofR³; and R³ is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl; R² is hydrogenor (C₁-C₆)alkyl; R⁴ and R⁵ are independently hydrogen or (C₁-C₆)alkyl;R⁶ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1or 2; W is (C₁-C₆)alkyl, or phenyl, optionally substituted by 1, 2, or 3Z; R_(a) to R_(g) are independently hydrogen or (C₁-C₄)alkyl; and R_(h)is H, (C₁-C₄)alkyl, or phenyl; or a pharmaceutically acceptable saltthereof; provided that R³ is not phenyl, when R¹ is methoxycarbonyl, R²is hydrogen, Y is NR⁶, and R⁶ is methyl.
 3. A compound of formula I:

wherein Y is —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f), orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof.
 4. The compoundof claim 1 wherein R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W; and R³is (C₆-C₁₀)aryl, 5-10 membered heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,5-10 membered heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl, or 5-10membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituentmay optionally be substituted on carbon by 1, 2 or 3 Z; or R¹ is —CH₂—,or —CH₂CH₂—, wherein R¹ is attached to a carbon at the ortho position ofR³; and R³ is (C₆-C₁₀)aryl, or 5-10 membered heteroaryl.
 5. The compoundof claim 1 wherein R¹ is —C(═O)OR_(a), cyano, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W.
 6. Thecompound of claim 1 wherein R¹ is cyano, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionallysubstituted at the 3-position by W.
 7. The compound of claim 1 whereinR¹ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.
 8. The compoundof claim 1 wherein R¹ is —C(═O)OR_(a); and R_(a) is (C₁-C₄)alkyl.
 9. Thecompound of claim 1, 2, or 3 wherein R² is hydrogen.
 10. The compound ofclaim 1, 2, or 3 wherein R³ is (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,or (C₆-C₁₀)arylcarbonyl, wherein any aryl substituent may optionally besubstituted on carbon by 1, 2 or 3 Z.
 11. The compound of claim 1, 2, 3,or 8 wherein R³ is 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or4-isopropenylphenyl.
 12. The compound of claim 1 or 2 wherein Y is NR⁶;and R⁶ is hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl.
 13. The compound ofclaim 1 wherein Y is NR⁶; R¹ is methoxycarbonyl, (C₁-C₆)alkyl, oracetoxymethyl; R² is hydrogen; and R³ is 4-chlorophenyl, 4-fluorophenyl,4-methylphenyl, or 4-isopropenylphenyl; and R⁶ is methyl.
 14. Thecompound of claim 1, 2, 3, or 4 wherein R¹ and R² are in a transconfiguration.
 15. The compound of claim 1 which istrans-1-methyl-4-(4-chlorophenyl)piperidine-3-carboxylic acid methylester.
 16. The compound of claim 1 which is (+)-methyl4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate.
 17. The compoundof claim 1 which is (−)4β-(4-chlorophenyl)-1-methyl-3β-n-propylpiperidine; or (+)4β-(4-chlorophenyl)-1-methyl-3α-n-propylpiperidine.
 18. A pharmaceuticalcomposition comprising a compound of formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f,) orS(═O)_(n)R_(g); and R³is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable diluent or carrier.
 19. A method comprisingtreating drug addiction in a human by administering a pharmaceuticallyeffective dose of a compound of formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f), orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof.
 20. The method ofclaim 18 wherein the drug is cocaine.
 21. A method comprising treating adisease or condition in a mammal in which the activity of dopamine orserotonin is implicated and modulation of dopamine or serotonin reuptakeis desired comprising administering a compound of formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f) orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof.
 22. The method ofclaim 20 wherein the disease is depression.
 23. The method of claim 20wherein the disease is Parkinson's disease.
 24. A radio labeled compoundcomprising a radionuclide and a compound of formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f) orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R¹ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof.
 25. A methodcomprising imaging the brain of a mammal by administering a radiolabeledcompound comprising a radionuclide and a compound of formula I:

wherein Y is NR⁶, —C(R⁴)(R⁵)—, or —O—; R¹ is —C(═O)OR_(a), cyano,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or 1, 2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, whereinany (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl mayoptionally be substituted by 1, 2 or 3 Z, wherein each Z isindependently halo, nitro, cyano, hydroxy, (C₁-C₆)alkoxy,(C₂-C₆)acyloxy, C(═O)OR_(b), C(═O)NR_(c)R_(d), NR_(e)R_(f) orS(═O)_(n)R_(g); and R³ is (C₆-C₁₀)aryl, 5-10 membered heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, 5-10 membered heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein anyaryl or heteroaryl substituent may optionally be substituted on carbonby 1, 2 or 3 Z; or R₁ is —CH₂—, or —CH₂CH₂—, wherein R¹ is attached to acarbon at the ortho position of R³; and R³ is (C₆-C₁₀)aryl, or 5-10membered heteroaryl; R² is hydrogen or (C₁-C₆)alkyl; R⁴ and R⁵ areindependently hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, or S(O)₂R_(h); n is 0, 1 or 2; W is (C₁-C₆)alkyl, orphenyl, optionally substituted by 1, 2, or 3 Z; R_(a) to R_(g) areindependently hydrogen or (C₁-C₄)alkyl; and R_(h) is H, (C₁-C₄)alkyl, orphenyl; or a pharmaceutically acceptable salt thereof; and detecting thepresence of the radiolabeled compound in the brain.
 26. The method ofclaim 25 wherein the radiolabeled compound is detected using positronemission tomography or single photon emission computerized tomography.